Axonal guidance occurs through the complex interplay of chemoattractant and chemorepellant factors that are capable of either guiding the growth cone toward an appropriate target or repelling a growth cone by causing it to collapse, such that innervation of inappropriate targets does not occur. One molecular mechanism responsible for such growth cone repulsion is signaling by semaphorins (Mark et al., Cell Tissues Res. 1997; 290(2): 2661-8; Raper, Curr. Opin Neurobiol, 2000; 10(1): 88-94). Semaphorins play a central role in mediating neuronal plasticity during embryonic development by acting as repulsive axonal guidance signals inducing collapse of growth cones (Puschel, Eur J Neurosci 1996; 8:1317-1321; Raper, Curr Opin Neurobiol 2000; 10:88-94).
As either a cell surface or secreted protein, Semaphorin 3A (Sema 3A) mediated by the intracellular effector, collapsin response mediator protein (CRMP), Quin et al., J Neurobiol 1999; 41(1): 158-64; Wang et al., J Neurosci 1996; 16(19): 6197-207), produces repulsive guidance by the reversible collapse of growth cones. An important element of the effects of Sema3A signaling is the role that it may play in regulating the neuronal population in the developing nervous system, matching afferent innervation to target requirements, resulting in programmed cell death of afferent neurons. It has been demonstrated in neural progenitor cells (Bagnard et al., J Neurosci 2001; 21(10): 3332-41), sensory (Gagliardini and Fankhauser, Mol Cell Neurosci 1999; 14:301-316), sympathetic, and cerebellar granule neurons (Shirvan et al., J Neurochemistry 1999; 73:961-71), known to express Sema3A in the developing nervous system, that administration of Sema3A in culture induces morphological and biochemical evidence of programmed cell death and apoptosis, resulting in neurodegeneration. A critical aspect of the studies by Shirvan and co-workers is the use of the model of dopamine induced oxidative stress, in which they identified the upregulation of both Semaphorin and CRMP-2, coincident with the induction of apoptosis in sympathetic neuronal cultures.
The chemorepulsive effects of Sema3A are transduced by a receptor complex containing the transmembrane proteins Neuropilin-1 and Plexin A1 or A2 (Takahashi et al., Cell 1999; 99:59-69; Rohm et al., Mech Dev 2000; 93:95-104), and the intracellular effector molecule collapsin response mediator protein 2 (CRMP-2) (Wang and Strittmatter, J Neurosci 1996; 16:6197-6207). Microinjection of the chick CRMP-2 homolog, CRM62, neutralizing antibodies into chick dorsal root ganglion has been shown to block chicken Sema3A-induced growth cone collapse, suggesting a direct role for CRMP-2 in Sema3A signaling cascades (Goshima et al., Nature 1995; 376:509-14).
The expression of phosphorylated p38, a downstream kinase of the mitogen-activated extracellular signal-regulated protein kinase, has also been examined in AD (Ferrer et al., J Neural Transam 2001; 108(12):1397-1415; Atorzi et al., J Neuropathol Exp Neurol 2001; 60(12):1190-97) and PD (Ferrer et al., J Neural Transm 2001; 108(120:1383-96). Immunohistochemical analysis revealed strong staining of phosphorylated p38 in about 50-70% of neurons with neurofibrillary tangles, and neuronal or glial cells that contained tau-positive deposits in both AD and PD. Both AD and PD are characterized by intracellular deposits of hyperphosphorylated tau, a microtubule-associated protein that is responsible for the formation of neurofibrillary tangles. However, in both AD and PD, analysis of apoptosis-related changes including DNA fragmentation, demonstrated that the expression of p38 was unrelated to activation of an apoptotic cascade.